title: Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.
abstract: OBJECTIVE
  It is uncertain whether modest benefits from adjuvant chemotherapy in stage II colorectal cancer justify the toxicity, cost, and inconvenience. We investigated the usefulness of defective mismatch repair (dMMR), BRAF, and KRAS mutations in predicting tumor recurrence and sensitivity to chemotherapy.
  
  
  METHODS
  Immunohistochemistry for dMMR and pyrosequencing for KRAS/BRAF were performed for 1,913 patients randomly assigned between fluorouracil and folinic acid chemotherapy and no chemotherapy in the Quick and Simple and Reliable (QUASAR) trial.
  
  
  RESULTS
  Twenty-six percent of 695 right-sided colon, 3% of 685 left-sided colon, and 1% of 407 rectal tumors were dMMR. Similarly, 17% of right colon, 2% of left colon, and 2% of rectal tumors were BRAF mutant. KRAS mutant tumors were more evenly distributed: 40% right colon, 28% left colon, and 36% rectal tumors. Recurrence rate for dMMR tumors was half that for MMR-proficient tumors (11% [25 of 218] v 26% [438 of 1,695] recurred; risk ratio [RR], 0.53; 95% CI, 0.40 to 0.70; P < .001). Risk of recurrence was also significantly higher for KRAS mutant than KRAS wild-type tumors (28% [150 of 542] v 21% [219 of 1,041]; RR, 1.40; 95% CI, 1.12 to 1.74; P = .002) but did not differ significantly between BRAF mutant and wild-type tumors (P = .36). No marker predicted benefit from chemotherapy with efficacy not differing significantly by MMR, KRAS, or BRAF status. The prognostic value of MMR and KRAS was similar in the presence and absence of chemotherapy.
  
  
  CONCLUSIONS
  MMR assays identify patients with a low risk of recurrence. KRAS mutational analysis provides useful additional risk stratification to guide use of chemotherapy.
authors.affiliation: Leeds Institute of Molecular Medicine, Leeds University, United Kingdom.
authors.forename: Gordon
authors.initials: G
authors.lastname: Hutchins
authors.forename: Katie
authors.initials: K
authors.lastname: Southward
authors.forename: Kelly
authors.initials: K
authors.lastname: Handley
authors.forename: Laura
authors.initials: L
authors.lastname: Magill
authors.forename: Claire
authors.initials: C
authors.lastname: Beaumont
authors.forename: Jens
authors.initials: J
authors.lastname: Stahlschmidt
authors.forename: Susan
authors.initials: S
authors.lastname: Richman
authors.forename: Philip
authors.initials: P
authors.lastname: Chambers
authors.forename: Matthew
authors.initials: M
authors.lastname: Seymour
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.forename: Richard
authors.initials: R
authors.lastname: Gray
authors.forename: Philip
authors.initials: P
authors.lastname: Quirke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004739:England; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D002955:Leucovorin / Q000008:administration & dosage; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis; D009154:Mutation; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000032:analysis; D016017:Odds Ratio; D018579:Patient Selection; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C117307:KRAS protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil